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Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition.

Cancer cell (2014-03-22)
Marcel Kool, David T W Jones, Natalie Jäger, Paul A Northcott, Trevor J Pugh, Volker Hovestadt, Rosario M Piro, L Adriana Esparza, Shirley L Markant, Marc Remke, Till Milde, Franck Bourdeaut, Marina Ryzhova, Dominik Sturm, Elke Pfaff, Sebastian Stark, Sonja Hutter, Huriye Seker-Cin, Pascal Johann, Sebastian Bender, Christin Schmidt, Tobias Rausch, David Shih, Jüri Reimand, Laura Sieber, Andrea Wittmann, Linda Linke, Hendrik Witt, Ursula D Weber, Marc Zapatka, Rainer König, Rameen Beroukhim, Guillaume Bergthold, Peter van Sluis, Richard Volckmann, Jan Koster, Rogier Versteeg, Sabine Schmidt, Stephan Wolf, Chris Lawerenz, Cynthia C Bartholomae, Christof von Kalle, Andreas Unterberg, Christel Herold-Mende, Silvia Hofer, Andreas E Kulozik, Andreas von Deimling, Wolfram Scheurlen, Jörg Felsberg, Guido Reifenberger, Martin Hasselblatt, John R Crawford, Gerald A Grant, Nada Jabado, Arie Perry, Cynthia Cowdrey, Sydney Croul, Gelareh Zadeh, Jan O Korbel, Francois Doz, Olivier Delattre, Gary D Bader, Martin G McCabe, V Peter Collins, Mark W Kieran, Yoon-Jae Cho, Scott L Pomeroy, Olaf Witt, Benedikt Brors, Michael D Taylor, Ulrich Schüller, Andrey Korshunov, Roland Eils, Robert J Wechsler-Reya, Peter Lichter, Stefan M Pfister

Smoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant.

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